Process for the preparation of bendamustine hydrochloride

a technology of bendamustine and hydrochloride, which is applied in the field of process for the preparation of bendamustine hydrochloride, can solve the problems of increasing the level of various process-related impurities, affecting the economic viability of the process, and difficulty in its preparation and administration

Active Publication Date: 2014-05-01
FRESENIUS KABI ONCOLOGY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0020]First aspect of the present invention provides an improved proces

Problems solved by technology

While bendamustine has been demonstrated as efficacious, it is known to be unstable, especially in aqueous solutions, leading to formation of non-bendamustine products (i.e. “degradation impurities”) which leads to technical difficulties in its preparation and administration.
The most of the prior art processes described above involveThe use of ethylene oxide for the preparation of bendamustine hydrochloride, which is often not suitable for industrial scale processes due to difficulty in handling ethylene oxide, since it is shipped as a refrigerated liquid.Further, the known processes involve the use of strongly acidic conditions and high temperatures for the hydrolysis of ethyl ester of bendamustine and subsequent in-situ formation of bendam

Method used

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  • Process for the preparation of bendamustine hydrochloride
  • Process for the preparation of bendamustine hydrochloride
  • Process for the preparation of bendamustine hydrochloride

Examples

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reference example-1

Preparation of Bendamustine Hydrochloride as Per Patent No. DD159877

[0085]Ethyl 4-[1-methyl-5-bis-(2-hydroxyethyl)-amino-benzimidazolyl-2]butanoate (4, 4.305 g) was added to chloroform (36 mL) and agitated till clear solution is formed. The solution was cooled to 0° C. Thionyl chloride (2.175 g) was added to the above solution within 40 minutes maintaining the temperature of the solution to 0-5° C. by cooling. The reaction mixture was agitated at 0-5° C. for 1 hour. The temperature was raised slowly to room temperature by removing cooling within 2.5 to 3 hrs and subsequently agitated at room temperature for 15 to 16 hrs. The solution was dispersed by agitating in 37.5 mL concentrated hydrochloric acid whereby the excessive thionyl chloride was decomposed under increased hydrochloric acid and SO2 development. The chloroform was distilled away and further stirred for 3 hrs at around 95° C. Activated carbon (0.78 g) was added to the solution and stirred for further 30 minutes at around...

example-1

Preparation of Ethyl 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III)

[0086]Ethyl 4-[5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (II, 40.0 g, 0.153 mol) was added to 2-bromoethanol (80 mL) and agitated for 15-30 minutes. Acetonitrile (80 mL) and calcium carbonate (61.3 g, 0.61 mol) were added to the reaction mixture. The reaction mixture was heated to 80-90° C. within 2 hours and refluxed at 80-90° C. for 34-38 hours. The reaction mixture was cooled to below 70° C. and acetonitrile (80.0 mL) was added. The reaction mixture was further cooled to 20-30° C. and filtered through celite prewashed with acetonitrile. The filtrate was concentrated at 50-60° C. under vacuum till viscous mass is obtained.

[0087]The viscous mass was cooled to 20-30° C. Dichloromethane (320.0 mL) was added to the viscous mass under stirring and washed with potassium carbonate solution (32.0 g in 200 mL water). The organic layer was washed with DM water twice. The organic layer (Di...

example-2

Preparation of Ethyl 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (IV)

[0088]4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III, 90.0 g, 1.15 mole) was added to dichloromethane (6.24 L) and agitated till clear solution is formed. A solution of thionyl chloride (292.3 g, 2.52 mol) in dichloromethane (1.56 L) was added slowly in 2 to 3 hours. After complete addition of thionyl chloride solution, reaction mixture was refluxed at 35-45° C. for 6 hours. The reaction mixture was cooled to 20-30° C. and 1.95 L dichloromethane was added. Potassium carbonate solution (351.0 g in 1.95 L water) was added to the reaction mixture slowly to control the evaluation of effervescence. The layers were separated. The organic (dichloromethane) layer was washed with brine solution. The organic layer was concentrated at 30-35° C. under vacuum till viscous mass is obtained. The viscous mass was dissolved in acetone (1.95 L) and DM water (1.365 L) was slowl...

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Abstract

The present invention relates to an improved process for the synthesis of bendamustine, in particular, bendamustine hydrochloride of the formula (VI) and its intermediate 1-Methyl-5-[bis(2-chloroethyl)amino]-1H-benzimidazol-2-yl]lithium butanoate of formula (V), both having a purity of ≧99%, which is simple, convenient, economical, does not use hazardous chemicals and industrially viable.

Description

[0001]The present invention relates to an improved process for the preparation of bendamustine, in particular, bendamustine hydrochloride and its intermediates, both having a purity of ≧99%, which is simple, convenient, economical and industrially viable.BACKGROUND OF THE INVENTION[0002]Bendamustine hydrochloride, 4-{5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid hydrochloride, of the formula (VI):was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there, as the hydrochloride salt, under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin®. Bendamustine Hydrochloride as injection is available in the United States under the tradename Treanda®. Bendamustine hydrochloride is an alkylating agent that is approved for the treatment of non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia.[0003]Bendamustine hydrochloride is a benzimidazo...

Claims

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Application Information

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IPC IPC(8): C07D235/16
CPCC07D235/16C07D407/04A61P35/00
Inventor MISHRA, BHUWAN BHASKARKACHHADIA, NIKUNJ SHAMBHUBHAITOMAR, VINOD SINGHLAHIRI, SASWATA
Owner FRESENIUS KABI ONCOLOGY LTD
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